Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.

中文翻译：

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脯氨酰羟化酶 2 失活可增强糖原储存并促进过度的中性粒细胞反应。

对感染的有效反应需要完全激活的先天免疫细胞，但它们的迅速失活和去除对于限制组织损伤至关重要。在这里，我们已经确定了脯氨酰羟化酶 Phd2 在维持适当的、主要是中性粒细胞介导的病原体清除和先天免疫反应消退之间的平衡中的关键作用。我们证明了骨髓特异性 Phd2 的缺失导致对肺炎链球菌的过度炎症反应，中性粒细胞运动、功能能力和存活率增加。这些增强的中性粒细胞反应依赖于糖酵解通量和糖原储存的增加。HIF-脯氨酰羟化酶抑制剂的全身给药复制了延迟炎症消退的Phd2缺陷表型。一起，这些数据将 Phd2 确定为常氧条件下中性粒细胞中的主要 HIF 羟化酶，并将糖酵解和糖原储存的内在调节与中性粒细胞介导的炎症反应的消退联系起来。这些结果证明了靶向代谢途径在治疗炎症性疾病中的治疗潜力。